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Clear cell SCC (CCSCC) is a rare histological variant of SCC, and various clear cell neoplasms must be considered in the differential diagnosis of CCSCC in the oral cavity. Based on a limited number of CCSCC cases reported in the oral cavity, CCSCC is considered an aggressive variant of SCC with a poor prognosis; however, its genetic characteristics remain unknown.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>A maxillary gingival tumor in an 89-year-old female was described and investigated using immunohistochemical staining, special staining, fluorescence in situ hybridization, and next-generation sequencing (NGS) with a custom panel of driver genes, including those associated with SCC and clear cell neoplasm development.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Histopathological examination revealed a proliferation of atypical epithelial cells with abundant clear cytoplasm and enlarged and centrally placed round nuclei. The tumor was exophytic with deep, penetrating proliferation. The atypical clear cells were continuous with the conventional SCC cells. Immunohistochemical analysis showed that the clear cells were positive for CK AE1\/AE3 and CK5\/6 and nuclear-positive for p63. In contrast, the clear cells were negative for \u03b1SMA, S100, HMB45, Melan-A, CD10, and p16. p53 immunoreactivity exhibited a wild-type expression pattern. Additionally, the clear cells were positive for periodic acid-Schiff (PAS) and negative for diastase-PAS, mucicarmine, and Alcian blue. Based on these results, the diagnosis of CCSCC was confirmed. Molecular analysis of the clear cells identified <jats:italic>PIK3CA<\/jats:italic> p.E542K (c.1624G&gt;A) and <jats:italic>HRAS<\/jats:italic> p.G12A (c.35 G&gt;C) somatic mutations classified as oncogenic. No pathogenic variants were identified in <jats:italic>TP53<\/jats:italic>, <jats:italic>EWSR1<\/jats:italic>, <jats:italic>AKT1<\/jats:italic>, <jats:italic>PTEN<\/jats:italic>, <jats:italic>BRAF<\/jats:italic>, <jats:italic>KRAS<\/jats:italic>, <jats:italic>NRAS<\/jats:italic>, <jats:italic>RASA1, or MAML2<\/jats:italic>.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We report a case of CCSCC of the oral cavity with <jats:italic>PIK3CA<\/jats:italic> and <jats:italic>HRAS<\/jats:italic> mutations. The identification of <jats:italic>PIK3CA<\/jats:italic> and\/or <jats:italic>HRAS<\/jats:italic> mutations is rare in SCC; however, both mutations are important potential targets for antitumor therapy. A detailed analysis of gene mutations in CCSCC may lead to a better understanding of its biological behavior and an improved prognosis, as well as a differential diagnosis from other clear cell neoplasms.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s12105-023-01580-8","type":"journal-article","created":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T18:02:11Z","timestamp":1695319331000},"page":"1026-1033","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Clear Cell Squamous Cell Carcinoma of the Maxillary Gingiva Associated with PIK3CA and HRAS Mutations: Report of a Case and Literature Review"],"prefix":"10.1007","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4148-1106","authenticated-orcid":false,"given":"Katsutoshi","family":"Hirose","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Shibahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akari","family":"Teramoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Usami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sawako","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Iwamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumei","family":"Murakami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Oya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narikazu","family":"Uzawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Motooka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Hori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiichi","family":"Morii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Toyosawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,9,21]]},"reference":[{"key":"1580_CR1","first-page":"108","volume-title":"World Health Organization classification of head and neck tumours","year":"2017","unstructured":"El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ (eds) (2017) World Health Organization classification of head and neck tumours, 4th edn. 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